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Hundie Tesfaye, Romana Branova, Eva Klapkova, Richard Prusa, Daniela Janeckova, Petr Riha, Petr Sedlacek, Petra Keslova, Josef Malis
(Department of Medical Chemistry and Clinical Biochemistry, Division of Clinical Pharmacology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic)
Ann Transplant 2014; 19:214-224
Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM.
Material and Methods: Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects. Busulfan concentrations were determined by high-performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule.
Results: We observed trough levels of 25–1244 µg/L, peak levels of 849–4586 µg/L, and AUC of 2225–12818 µg/L·h following body weight-based high-dose busulfan. The doses were changed in 54% of cases.
AUC in 5 of 9 patients with VOD were within target, in 3 patients AUS was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC. Engraftment was 100%, but relapse occurred in 25% of cases.
Conclusions: Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging. Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM.
Keywords: High Dose Busulfan Target AUC, Limited Sampling Strategy TDM, Paediatric HSCT